Brugada syndrome BS is a

Brugada syndrome (BS) is a hereditary arrhythmogenic disease characterized by a coved- or saddleback-type ST elevation in the right precordial lead on a 12-lead electrocardiogram (ECG) and ventricular fibrillation (VF) occurring mainly at night. During the past 2 decades, since Brugada and Brugada first described this peculiar condition, there has been notable progress in our understanding of this syndrome with respect to genetics, epidemiology, electrophysiology, and clinical findings. Hundreds of mutations in more than 12 genes that encode sodium, potassium, or calcium ion hedgehog inhibitor have been identified in individuals with this condition. The prevalence, incidence, and short-term prognosis of this syndrome have also been clarified. However, the exact reason for its predominance in men and Asian individuals remains unknown, although the effect of testosterone and the higher expression of the transient outward potassium (Ito) current in the right ventricular (RV) epicardium in men and polymorphisms that are found only in Asian individuals are believed to be responsible for this predominance. The pathophysiological mechanism of this syndrome also remains a matter of debate. There are 2 main theories that explain the mechanism of ST elevation and ventricular arrhythmias: the repolarization hypothesis and the depolarization hypothesis. The repolarization hypothesis has been supported by studies using animal models and relies on Ito-mediated transmural dispersion of repolarization between the RV endocardium and epicardium. This theory provides an explanation for the trigger (phase 2 reentry) underlying the development of VF, ST segment elevation by calcium channel blockers or potassium channel openers, ST segment normalization by quinidine or isoproterenol, and the strong association between spontaneous type 1 ECG and cardiac events. In contrast, the depolarization hypothesis relies on conduction delay in the RV outflow tract caused by structural abnormalities. Although this theory has not been demonstrated in experimental models, various data supporting the existence of RV conduction delay have been obtained from electrophysiological studies (EPS) and clinical studies involving signal-averaged ECGs and body surface, epicardial, and endocardial mapping. Furthermore, Nademanee et al. recently demonstrated that abnormal low-voltage, prolonged, and fractionated late potentials exist in the epicardial aspect of the RV outflow tract in selected BS patients who received multiple shocks by an implantable cardioverter-defibrillator (ICD). It is unknown whether these abnormalities exist in every BS patient and which hypothesis is more reliable. Further research is needed to clarify these issues as well as to determine the efficacy of catheter ablation in patients with BS. The value of VF inducibility by EPS is still a controversial topic for risk stratification in BS. Although many studies have failed to demonstrate the usefulness of EPS, a good association between VF inducibility and patient outcome may be obtained by using specific standardized stimulation protocols, as reported by Makimoto et al. .
Introduction Brugada syndrome (BS) is a clinical entity that causes sudden death because of ventricular fibrillation (VF) in patients with apparently structurally normal hearts, and it is characterized by coved ST-segment elevation in the right precordial leads (V1–V3) [1,2]. A similar clinical condition, which brings sudden death mainly at night in young and middle-aged men, has been known in Asian countries by different names such as “pokkuri” in Japan, “lai-tai” in Thailand, and “bangungut” in the Philippines. Several cases of pokkuri or idiopathic VF that showed coved ST elevation just after resuscitation were reported in Japan [3,4] in 1990 (Fig. 1) before Brugada et al. first described this condition in 1992. In 1990, we also reported that some patients demonstrate a peculiar ST elevation in the leads V1–V3 and develop a syncopal attack at midnight or early morning in a series of four cases with idiopathic VF [4]. With respect to the ST elevation in the precordial lead, Antzelevitch et al. demonstrated that this can be an expression of early repolarization or J-wave caused by transient outward current (Ito)-mediated transmural differences in the early phases of the action potential. BS is an inherited disease with a heterogeneous genetic basis [5]. More than 11 genes have been linked to this disease in the last 15 years, although mutations in SCN5A are the most commonly found mutations in 15–30% of Brugada patients.
Prevalence of Brugada syndrome in Japan BS is responsible for 4% of all sudden deaths and for up to 20% of sudden deaths in patients without structural heart disease [2,6]. The estimated prevalence of BS ranges from 4 to 122 per 10,000 inhabitants in Japan. However, many of these reports were published before 2002 when the consensus report for BS was proposed [7]; thus, the 12-lead electrocardiogram (ECG) definition in many reports included not only the coved ST elevation but also the saddleback ST elevation with a J-wave of amplitude ≥1mm (0.1mV). Furthermore, right bundle branch block (RBBB) was considered to be an essential ECG feature for BS at that time. Miyasaka et al. reported that the coved ST elevation ≥1mm with RBBB was found in 0.12% of 13,929 subjects, with a prevalence of 0.38% in men and 0.03% in women, who were screened during annual health examinations in Moriguchi-city, Osaka [8]. They also indicated that Brugada-pattern ECG was recognized in 0.7% of all subjects but was higher in men (2.14%) when saddleback ST elevation ≥1mm was also included in the Brugada-pattern. In the same study cohort in Moriguchi, Tsuji et al. later reported that 0.26% of subjects demonstrated type 1 Brugada-pattern ECG with or without RBBB [9]. Atarashi et al. evaluated 10,000 ECGs obtained during annual check-ups of working adults in the Tokyo area and found that 16 men (0.16%) showed coved-type ST elevation ≥1mm with RBBB in the right precordial leads [10]. In addition, Matsuo et al. reported that the prevalence of Brugada-pattern ECG with coved or saddleback ST elevation ≥1mm was 0.146% in a survey of ECG records of 4788 atomic-bomb survivors who underwent biennial health examination for 40 years in Nagasaki [11]. Furuhashi et al. also reported that the prevalence of Brugada-pattern ECG was 0.14% in 8612 healthy subjects [12]. A report with an inclusion criterion for Brugada-type ECG of ST elevation >2mm with or without RBBB was published by Sakabe et al. [13]. They evaluated ECGs of 3339 healthy adult subjects who underwent medical examinations annually from 1992 to 2001 and reported that an average 0.28% of subjects showed coved-type ST elevation in the right precordial lead. They also indicated that the majority (97%) of subjects who showed coved-type or saddleback-type ST elevation (1.22%) were men.